GATA4 as a Modulator of Aortic Root Sensitivity to Mechanochemical Disruptions Caused by an Aneurysm-causing Mutation

项目总结 主动脉瘤是局部扩张，使血管容易夹层或破裂，两者都是 与高死亡率有关。Loeys-Dietz综合征(LDS)是一种遗传性动脉瘤疾病，由 会损害但不会完全破坏转化生长因子-β信号的突变。腰椎间盘突出症患者有很强的易感性 主动脉根部的疾病，尽管在这种情况下突变的基因普遍表达 贯穿整个血管系统。这种局部性漏洞背后的机制尚不清楚。在这 提议，我将检验这一假设，即在平滑肌细胞中表达的内在因子存在于 主动脉根部使其更容易受到以下因素引起的主动脉机械力化学破坏的影响 LDS突变。具体地说，我将研究Gata4在血管平滑的一个子集中是否固有表达 肌肉细胞启动这些细胞以上调GATA4，当依赖于 这些细胞与细胞外基质之间的适当接触失败。我将得到我的赞助人Dr。 麦克法兰博士和共同赞助人迪茨博士共同完成了以下目标。在目标1中，我将揭示LDS是如何 突变影响主动脉局部粘连下游的细胞外基质结构和信号转导 药物干预对这些通路在动脉瘤发病机制中的作用。在《目标2》中，我会 通过检测出生后GATA4的作用阐明GATA4在主动脉根部动脉瘤发病机制中的作用 平滑肌特异性缺失Gata4对主动脉根部扩张的影响。在我的合作者的帮助下， 香原，谁是空间转录学的专家，我也将学习使用这种尖端技术和 相关的计算工具，以绘制沿主动脉长度的转录异质性的梯度。我 将进一步发展我作为一名独立研究员的技能，并增强我在心血管方面的专业知识 通过完成有重点的课程作业和定期参加科学会议并在科学会议上发表演讲来学习生物学。至 提高我的科学交流能力，我将寻找更多的指导和教学机会， 包括在约翰·霍普金斯大学教授本科生遗传学课程。通过完成此操作 建议，我将获得必要的经验和技能，以获得博士后研究员的职位，并 最终在心血管研究领域建立独立的学术生涯。

PROJECT SUMMARY Aortic aneurysms are localized dilations that predispose the vessel to dissection or rupture, both of which are associated with high mortality. Loeys-Dietz Syndrome (LDS) is a hereditary aneurysm disorder caused by mutations that impair, but do not fully disrupt, TGF-β signaling. LDS patients have a strong predisposition for disease in the aortic root even though the genes that are mutated in this condition are ubiquitously expressed throughout the vasculature. The mechanisms that underlie this localized vulnerability remain unclear. In this proposal, I will test the hypothesis that intrinsic factors expressed in smooth muscle cells present in the aortic root render them more susceptible to the mechanochemical disruptions of the aorta caused by LDS mutations. Specifically, I will investigate if intrinsic expression of Gata4 in a subset of vascular smooth muscle cells primes these cells to upregulate GATA4 when homeostatic inhibitory mechanisms that depend on proper contacts between these cells and the extracellular matrix fail. I will be supported by my sponsor, Dr. MacFarlane, and co-sponsor, Dr. Dietz, to complete the following aims. In Aim 1, I will uncover how LDS mutations affect aortic extracellular matrix structure and signaling downstream of focal adhesions and examine the effect of pharmacological interference with these pathways on aneurysm pathogenesis. In Aim 2, I will clarify the role of GATA4 in the pathogenesis of aortic root aneurysm by examining the effect of postnatal smooth muscle specific deletion of Gata4 on aortic root dilation. With the help of my collaborator, Dr. Kagohara, who is an expert in spatial transcriptomics, I will also learn use this cutting-edge technology and related computational tools to map the gradient of transcriptional heterogeneity along the length of the aorta. I will further develop my skills as an independent researcher and enhance my expertise in cardiovascular biology by completing focused coursework and regularly attending and presenting at scientific conferences. To improve my skills in scientific communication, I will seek out additional mentoring and teaching opportunities, including teaching an undergraduate genetics course at Johns Hopkins University. By completing this proposal, I will acquire the experience and skills necessary to attain a position as a postdoctoral fellow, and ultimately establish an independent academic career in cardiovascular research.